TAG: "Cancer"

Gift will advance breakthroughs in pancreatic cancer research.

By Mary Goodstein, UCLA

UCLA celebrated the naming of the UCLA Agi Hirshberg Center for Pancreatic Diseases on Feb. 28 at a gathering of Hirshberg’s family and friends. The naming was made possible by $10 million in gifts from Hirshberg to UCLA.

“Agi Hirshberg’s 18-year commitment to finding a cure has placed UCLA at the forefront of cutting-edge research on pancreatic cancer,” said UCLA Chancellor Gene Block. “In recognition of her visionary support and a generous new $5 million gift, we are pleased to name the UCLA Agi Hirshberg Center for Pancreatic Diseases.”

The campus event also was attended by UCLA faculty and staff as well as members of Women and Philanthropy — of which Hirshberg is president — and the board of visitors of the David Geffen School of Medicine at UCLA.

Hirshberg established the Hirshberg Foundation for Pancreatic Cancer Research in 1997 in memory of her late husband, Ronald S. Hirshberg, who died of pancreatic cancer at age 54. The innovative research supported by the foundation has changed the face of pancreatic cancer treatment. As the first beneficiary of the foundation’s giving, UCLA established the Ronald S. Hirshberg Translational Pancreatic Cancer Research Laboratory in 1998 and the Ronald S. Hirshberg Chair in Translational Pancreatic Cancer Research in 2000.

Funding from the Hirshberg Foundation has elevated the UCLA center to one of the nation’s premier comprehensive programs for pancreatic cancer and diseases, and it has laid the groundwork for a model in which the needs of people with pancreatic cancer are met in one location with the most advanced treatment options available.

“I strongly believe that the cure for pancreatic cancer is right around the corner. I feel it,” Hirshberg said. “This new commitment ensures continuous research results and allows us to continue on our path toward a cancer-free life.”

Hirshberg’s most recent gift will fund seed grants as well as the center’s highest-priority needs. The Hirshberg Foundation’s Seed Grant Program has helped propel pancreatic cancer research, serving as a springboard for multiple investigations at UCLA and other prestigious institutions and leading to additional investments from the National Institutes of Health and other organizations. Since the program’s inception in 2000, it has generated more than $65 million in additional support for research involving the molecular mechanisms of pancreatic cancer, early diagnosis, surgical and chemotherapeutic treatments, psychosocial approaches to disease management and prevention strategies.

“Agi Hirshberg raised the visibility of this devastating disease and has been instrumental in advancing pancreatic cancer research, not only at UCLA but across the nation,” said Dr. Vay Liang Go, director of the UCLA Center for Excellence in Pancreatic Diseases. “Her ongoing support of the multiple areas focused on pancreatic cancer at UCLA has led to pioneering investigations that have given many patients a chance to survive one of the most deadly forms of cancer.”

According to Dr. Howard Reber, distinguished professor of surgery emeritus, chief of gastrointestinal and pancreatic surgery, and director emeritus of the newly renamed center, “Agi Hirshberg has had a major role in the growth and development of one of the country’s busiest and most successful clinical programs for the multidisciplinary treatment of pancreatic cancer.”

Kathryn Carrico, UCLA’s assistant vice chancellor for health sciences development, said, “We applaud not only Agi’s vision, dedication and leadership, but also the power of her philanthropy.”

UC San Francisco has received a $100 million gift from visionary philanthropist Charles F. “Chuck” Feeney to support its new Mission Bay hospitals, world-class faculty and students, and research programs focused on the neurosciences and aging.

This donation brings the longtime supporter’s total UCSF giving to more than $394 million, making Feeney the single largest contributor to the University of California system.

“I get my gratification from knowing that my investments in medical research, education, and the delivery of health care at UCSF will provide lifelong benefits to millions of people not only in the Bay Area but also around the world,” said Feeney, who, despite his global presence as a successful entrepreneur and discerning philanthropist, prefers remaining out of the limelight. “I can’t imagine a more effective way to distribute my undeserved wealth.”

Reflecting on Feeney’s contributions, UCSF Chancellor Sam Hawgood, M.B.B.S., said, “As we celebrate UCSF’s 150th anniversary this year, it is only fitting that we acknowledge the unique role Chuck has played in our history. While his impact has been felt most profoundly during this past decade, his generosity will carry on forever at our university, in the San Francisco community, throughout the Bay Area and globally, as our faculty and students advance knowledge and provide the finest clinical care. We are honored that he has decided to invest again in UCSF.”

Feeney’s gifts to UCSF are most visible at the university’s Mission Bay campus, where he has provided indispensable support to create advanced facilities and foster the environment for the biomedical research and patient care that goes on within them.

Before the latest funding, Feeney’s most recent gift to the campus was to UCSF Global Health Sciences, enabling the October 2014 opening of Mission Hall, which houses global health researchers, scientists and students under the same roof for the first time. Feeney, who coined the term “giving while living,” also generously supported the building of the Smith Cardiovascular Research Building and the Helen Diller Family Cancer Research Building.

“Chuck Feeney has been our partner at Mission Bay for more than 10 years,” added Hawgood. “He immediately embraced the Mission Bay concept, and he has enthusiastically helped us shape a larger vision for the campus and finance its development because he knew that our research and clinical programs could not flourish without state-of-the-art buildings.”

Gift to support four primary areas

The Campaign for the UCSF Medical Center at Mission Bay
Funds will support the $600 million philanthropy goal of the $1.5 billion hospitals project. The latest donation builds upon the transformative $125 million matching gift Feeney made to support the hospitals complex and its programs in 2009, the largest gift received toward the campaign.

“It’s been thrilling to see the reactions of our patients and their families as they encounter the amazing care offered at our new UCSF Mission Bay hospitals,” said Mark Laret, CEO of UCSF Medical Center and UCSF Benioff Children’s Hospitals. “This world-class experience would never have been possible without the support of Chuck Feeney who, as the largest contributor to the project, helped us create the hospitals of our dreams. Every patient cured, every breakthrough discovered at Mission Bay, will be thanks in part to Chuck. His legacy is unparalleled.”

Neuroscience and aging
The gift also supports UCSF’s pre-eminent neuroscience enterprise, including its Sandler Neurosciences Center and neurology programs at Mission Bay.

The center, a five-story, 237,000-square-foot building that opened in 2012, brings under one roof several of the world’s leading clinical and basic research programs in a collaborative environment. UCSF’s neurology and aging efforts are focused on finding new diagnostics, treatments, and cures for a number of intractable disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, migraine, epilepsy and autism. The programs also seek to integrate neuroscience and clinical disciplines with public health initiatives in order to disseminate and implement novel findings from research centers of excellence, as well as conduct community outreach to raise awareness about the diseases of aging.

“Chuck Feeney has taken a keen interest in the challenges of aging,” said Hawgood. “In turn, he has recognized UCSF’s extraordinary talent in the neurosciences, among both basic researchers and those who translate research into clinical care and public policy. This gift will build on UCSF’s strengths while encouraging strong partnerships at other research institutions around the world where Chuck also has made important investments.”

Student scholarships and housing
Even with its extraordinary academic firepower, UCSF has extremely limited funds to support scholarships for professional students in its schools of dentistry, medicine, nursing and pharmacy. Part of the gift will provide scholarship support, bolstering UCSF’s ability to recruit the best and brightest students, regardless of their financial circumstances.

Recent decreases in state funding led to tuition increases and higher demand for scholarships. This, in turn, increased student debt. Combined with Bay Area housing prices that are among the highest in the nation – from 2011 to 2013, the median rent increased by 24 percent – the prospect of overwhelming debt can deter economically vulnerable students as well as those from middle-class backgrounds from attending UCSF. By minimizing debt upon graduation, the scholarships will help ensure that a UCSF education remains in reach for students from underserved populations, as well as for those students who choose to become health care leaders in underserved communities.

“Scholarships give our students the gift of freedom: to make career choices based on purpose and passion, rather than the price of education; to use time to study, explore science, and volunteer to help others, rather than working to make ends meet; and to succeed because someone who never met them saw enough potential to invest in their dreams,” said Catherine Lucey, M.D., vice dean for education at UCSF’s School of Medicine. “These scholarships catalyze our schools’ ability to find, recruit, educate and nurture the workforce our country needs: talented professionals whose life experiences enable them to provide compassionate care to today’s diverse communities and advance science to improve the health of future communities.”

Faculty recruitment
The donation also will help UCSF recruit the next generation of promising faculty in an increasingly competitive marketplace.

New funding will attract junior faculty – who frequently find it more challenging to secure research funding – and provide initial startup funds as they launch their research careers and clinical practices. With decreasing federal support for young investigators, this gift will underwrite a new generation of brilliant upcoming faculty.

“While Chuck’s unprecedented generosity has been focused primarily on Mission Bay, he understands the power of the entire UCSF enterprise, from our cutting-edge stem cell research at Parnassus to our innovative cancer programs at Mount Zion,” Hawgood said. “We’re thrilled that Chuck has inspired other philanthropists to join him in creating one of the most vibrant life science communities in the world, where progress will ripple far beyond Mission Bay and the campus for generations to come.”

With 40 ambulances, approximately 300 UCSF staff and faculty, as well as 100 emergency medical services personnel, UCSF Medical Center on Sunday, Feb. 1, safely transported 131 patients to the new UCSF Medical Center at Mission Bay from its Parnassus and Mount Zion campuses.

The move day started at 7 a.m. on the UCSF Parnassus campus; later in the day patients also were transported from the UCSF Mount Zion campus. The last patient to be moved arrived at UCSF Medical Center at Mission Bay at 3:33 p.m. The new medical center also greeted the first baby born at the new hospitals, a healthy boy who entered the world at a little more than seven pounds.

The move day, itself, reflected significant planning. “Patient safety was our top priority during the patient move, along with minimizing disruption to our neighbors. We achieved both goals, thanks to the superb work of our medical center faculty and staff as well as our partners in the City of San Francisco,” said Mark R. Laret, CEO of UCSF Medical Center and UCSF Benioff Children’s Hospitals. “We have been looking forward to this day for some time, and the opportunity to start providing care in our new location at UCSF Mission Bay.”

The majority of patients who made the trip on Sunday were children, as UCSF Benioff Children’s Hospital San Francisco moved from Parnassus to its new home at UCSF Mission Bay.

Strategically located on UCSF’s world renowned UCSF Mission Bay biomedical research campus, the new medical center puts UCSF physicians in close proximity to UCSF researchers and nearby biotechnology and pharmaceutical companies in Mission Bay and beyond who are working to understand and treat diseases ranging from cancer to cardiovascular disease to neurological conditions.

“Placing the hospitals on our Mission Bay campus underscores our commitment to driving discoveries toward patient care, ensuring that our world-class researchers are working in close proximity to our leading clinical researchers and physicians in the hospitals,“ said Sam Hawgood, M.B.B.S., chancellor of UC San Francisco. “They also will provide invaluable training for our medical students, the next generation of clinicians who will take care of patients at health care facilities across California and nationally.

“Significantly, the move also frees up space on our Parnassus and Mount Zion campuses, which will allow us to enrich our medical programs for adult patients there. With the opening of the hospitals at Mission Bay, we now have integrated clinical care and research programs on all of our campuses, the critical factor that has contributed to UCSF’s local, regional and global impact.”

The UCSF Parnassus campus will be restructured to provide more specialized clinical services, such as transplants, and the UCSF Mount Zion campus will become a world-class hub for outpatient care.

“UCSF Medical Center’s new $1.5 billion, state-of-the-art campus in our city’s Mission Bay neighborhood will help improve the health of children, women and cancer patients,” said San Francisco Mayor Ed Lee. “This is not just a milestone for UCSF; this is a milestone for our city and our city’s health care industry, which is at the heart of our economy providing good jobs for our residents.

“Right before our eyes, we have seen the transformation of this underutilized railyard in Mission Bay into an epicenter where new discoveries and innovation in medicine are saving lives around the world. By working together with our great partner UCSF, and the many generous philanthropists that helped build these new hospitals, we will continue to ensure our residents get the highest quality of health care.”

HIGD1A may be a novel target for cancer therapy.

By Pete Farley, UC San Francisco

Tumor recurrence following a period of remission is the main cause of death in cancer. The ability of cancer cells to remain dormant during and following therapy, only to be reactivated at a later time, frequently with greater aggressiveness, is one of the least-understood aspects of the disease.

UCSF researchers working in the laboratory of Emin Maltepe, M.D., Ph.D., associate professor of pediatrics, led by associate research specialist Kurosh Ameri, Ph.D., have now identified a protein that plays a critical role in this process.

Tackling resistant cancer cells

Solid tumors have a core composed of necrotic, or dying, cells. Ameri and colleagues concentrated on the part of tumors that immediately surrounds these necrotic cores, which is known as the perinecrotic region.

Cancer cells in the perinecrotic region have traditionally been more difficult to eradicate than those nearer to the tumor surface, because they are deprived of both oxygen and nutrients – factors that promote resistance to therapy.

A classic regulator of cellular responses to low-oxygen conditions is the transcription factor known as hypoxia-inducible factor 1, or HIF-1. Perinecrotic regions paradoxically lack HIF-1 activity, but they retain expression of a small subset of HIF target genes.

The authors of the new study found that the protein product of one of these genes, a mitochondrial protein called HIGD1A, enables cells to survive in the extreme environment deep in the tumor by repressing their metabolism and the production of toxic reactive oxygen species (ROS).

Key protein represses tumor growth

When the scientists engineered tumors to overexpress HIGD1A, the tumors dramatically repressed their growth, as the team reported in the Feb. 17 issue of Cell Reports. But the overall survival of the tumor cells was significantly enhanced, and these effects were even seen in mice that lacked the HIF-1 protein.

To discern the mechanisms behind these effects, the authors looked for interactions between HIGD1A and other mitochondrial proteins. They found that it interacted with components of the electron transport chain responsible for oxygen consumption as well as ROS production. Expression of the HIGD1A protein reduced oxygen consumption but triggered increased mitochondrial ROS formation, which resulted in the activation of cellular antioxidant mechanisms driven by another critical metabolic regulatory protein, AMP-dependent kinase, or AMPK.

Surprisingly, the researchers found that the HIGD1A gene is not activated by hypoxia, or oxygen deprivation, in human cancers, even though the gene recruits HIF-1 to its promoter region. A lack of HIGD1A expression in response to hypoxia alone was due to increased methylation of the HIGD1A gene’s regulatory regions, which could be overcome in experiments either by applying pharmacological DNA-demethylating agents, or by combined oxygen/glucose deprivation, conditions that simulate the perinecrotic environment.

These data suggest that HIGD1A plays an important role in tumor dormancy mechanisms and may be a novel target for cancer therapy. Severe oxygen and nutrient deprivation decreases the levels of the enzyme DNA methyltransferase in multiple human cancers, allowing HIGD1A expression, and may represent a widespread mechanism enabling tumor cell survival in these HIF-deficient extreme environments.

The therapeutic promise of human stem cells is indisputably huge, but the process of translating their potential into effective, real-world treatments involves deciphering and resolving a host of daunting complexities.

Writing in today’s (Feb. 25) online issue of the journal PLOS ONE, researchers at the UC San Diego School of Medicine, with collaborators from The Scripps Research Institute (TSRI), have definitively shown for the first time that the culture conditions in which stem cells are grown and mass-produced can affect their genetic stability.

“Since genetic and epigenetic instability are associated with cancers, we worry that similar alterations in stem cells may affect their safety in therapeutic transplants. Certain mutations might make transplanted stem cells more likely to form tumors, introducing the risk of cancer where it didn’t exist before,” said co-corresponding author Louise Laurent, M.D., Ph.D., assistant professor and director of perinatal research in the Department of Reproductive Medicine at UC San Diego School of Medicine.

“This study shows the importance of quality control,” added Jeanne F. Loring, Ph.D., professor and director of the Center for Regenerative Medicine at TSRI, and adjunct professor in the UC San Diego Department of Reproductive Medicine and the study’s other co-corresponding author. “It’s almost certain these cells are safe, but we want to make sure they are free from any abnormalities.”

To exploit the transformative powers of human pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, requires producing them in large numbers for transplantation into patients.

“During this culturing process, mutations can occur, and mutations that increase cell survival or proliferation may be favored, such that the cells carrying such mutations could take over the culture,” said Laurent.

Human pluripotent stem cells are cultured in several different ways. Key variables are the surfaces upon which the cells are cultured, called the substrate, and the methods used to transfer cells from one culture dish into another as they grow, called the passage method.

Originally, scientists determined that stem cells grew best when cultured atop of a “feeder” layer that included other types of cells, such as irradiated mouse embryonic fibroblasts. For reasons not fully understood, these cells provide stem cells with factors that support their growth. However, concerns about the feeder cells also introducing undesirable materials into stem cells has prompted development of feeder-free cultures.

Moving cells from one culture dish to another has traditionally been done manually, with technicians physically separating the cultured cells into small clumps with an instrument. “It’s very labor-intensive,” said Laurent, “so new methods that use enzymes to separate individual cells were created.”

In the PLOS ONE paper, Laurent and colleagues compared stem cells grown on two substrates (with and without feeder cells) and passaged using manual and enzymatic methods. They report that the use of enzymes to passage the stem cells was strongly associated with increased genetic instability. Some of the mutations observed in the stem cells were previously known, but Laurent said others were seen for the first time, including deletion of a region of the genome that includes the gene P53, which is frequently deleted in cancer cells.

“I think these results call into question the use of enzymatic passaging, at least with enzymes that separate the cultures into single cells, for clinical use. However, we don’t want to imply that any culture method is absolutely ‘safe.’ Any new culture method should be evaluated for its impact on genetic stability, and every batch of cells destined for the clinic should be tested using sensitive high-resolution methods for detecting genetic alterations.

“The processes used to maintain and expand stem cell cultures for cell replacement therapies need to be improved, and the resulting cells must be carefully tested before use.”

Funding for this research came, in part, from the California Institute for Regenerative Medicine (grants CL1-00502, RT1-01108, TR1-01250, RM1-01717, TB1-01193, TG2-01165), the National Institutes of Health (grants R33MH087925, P01GM085354, P01HL089471), the UC San Diego Department of Reproductive Medicine, the Hartwell Foundation, the Millipore Foundation, the Esther O’Keefe Foundation, the Marie Mayer Foundation, Autism Speaks, the Pew Charitable Trust and the Wellcome Trust.

Almost all injuries, even minor skin scratches, trigger an inflammatory response, which provides protection against invading microbes but also turns on regenerative signals needed for healing and injury repair – a process that is generally understood but remains mysterious in its particulars.

Writing in today’s (Feb. 25) online issue of Nature, an international team of scientists, headed by researchers at the University of California, San Diego School of Medicine, report finding new links between inflammation and regeneration: signaling pathways that are activated by a receptor protein called gp130. “We found that gp130 is capable of activating several signaling pathways that turn on a number of transcription factors known to have a key role in stem cell biology,” said the study’s lead author, Koji Taniguchi, M.D., Ph.D., assistant project scientist in the Department of Pharmacology at UC San Diego.

These transcription factors – specifically STAT3, YAP and Notch – stimulate the proliferation and survival of normal tissue stem cells, which lead to healing and repair, said senior author Michael Karin, Ph.D., Distinguished Professor Pharmacology and Pathology and head of UC San Diego’s Laboratory of Gene Regulation and Signal Transduction.

“While the work was mainly conducted on a mouse model of intestinal injury, similar to the one that underlies human inflammatory bowel disease (IBD), we provide evidence that the same mechanism may control liver regeneration, which suggests a general role in tissue repair,” said Karin.

In addition to explaining a key biomedical phenomenon, the researchers said the findings have important clinical implications for the treatment of IBD and colorectal cancer. The major signal sensed by gp130 is the inflammatory hormone (cytokine) IL-6 and closely related proteins. Expression of IL-6 has been found to be elevated in IBD, both in Crohn’s disease and ulcerative colitis, giving rise to the possibility that inhibition of IL-6 binding to its receptor – a complex between gp130 and a specific IL-6 binding protein – may ameliorate the pathology of IBD.

But just the opposite has been observed. Drugs that block the binding of IL-6 to its receptor complex actually increase the risk of intestinal perforation and bleeding, making them unsuitable for the treatment of IBD. The new work suggests that IL-6 and the signaling pathways it stimulates are not the cause of IBD, but are part of the natural protective reaction to the initial injury and inflammatory response associated with the onset of IBD.

The Taniguchi and Karin team say it is important that future treatments not interfere with the healing response triggered by IL-6 and gp130. Nonetheless, the same pathways involved in healing and regeneration can go awry and become chronically stimulated in colorectal cancer.

The new work defines several molecular targets suitable for development of new targeted therapies for this very common malignancy – the third leading cause of cancer-related death, though Karin cautioned that “such treatments should not be combined with conventional and highly toxic anti-cancer drugs whose major side effect is damage and inflammation of the intestinal mucosa, a disease known as mucositis that will only be exacerbated by blocking the regenerative response triggered by IL-6.”

UCLA team analyzes data for more than 37,000 patients.

By Reggie Kumar, UCLA

UCLA researchers have found that radiation therapy is the most common treatment for men with prostate cancer regardless of the aggressiveness of the tumor, the risk to the patient or the patient’s overall prognosis. This finding lays the groundwork for doctors to make more informed decisions about treatment options and provide better information for people with the disease.

A team led by Dr. Karim Chamie, an assistant professor of urology at UCLA, analyzed data from 2004 through 2007 for more than 37,000 patients. They found that radiation therapy was the most common treatment for prostate cancer, and that the most significant factor in determining whether a man received radiation therapy was that he had been referred to a radiation oncologist. Urologists and surgeons, on the other hand, took into account the patient’s age and health as well as the aggressiveness of the cancer before recommending surgery.

“Doctors and patients view radiation as safe,” Chamie said. But he added that by two years after treatment, men often start to suffer side effects including urinary incontinence, bowel dysfunction, erectile dysfunction and radiation cystitis.

According to the report, those side effects and risks might be outweighed by the benefits of radiation for patients with aggressive cancer and otherwise long life expectancy. But for a patient with a slow-growing tumor and shorter life expectancy, radiation might not be worthwhile.

In greater than 90 percent of cases in which treatment for metastatic cancer fails, the reason is that the cancer is resistant to the drugs being used. To treat drug-resistant tumors, doctors typically use multiple drugs simultaneously, a practice called combination therapy. And one of their greatest challenges is determining which ratio and combination — from the large number of medications available — is best for each individual patient.

Dr. Dean Ho, a professor of oral biology and medicine at the UCLA School of Dentistry, and Dr. Chih-Ming Ho, a professor of mechanical engineering at the UCLA Henry Samueli School of Engineering and Applied Science, have developed a revolutionary approach that brings together traditional drugs and nanotechnology-enhanced medications to create safer and more effective treatments. Their results are published in the peer-reviewed journal ACS Nano.

Chih-Ming Ho, the paper’s co-corresponding author, and his team have developed a powerful new tool to address drug resistance and dosing challenges in cancer patients. The tool, Feedback System Control.II, or FSC.II, considers drug efficacy tests and analyzes the physical traits of cells and other biological systems to create personalized “maps” that show the most effective and safest drug-dose combinations.

Currently, doctors use people’s genetic information to identify the best possible combination therapies, which can make treatment difficult or impossible when the genes in the cancer cells mutate. The new technique does not rely on genetic information, which makes it possible to quickly modify treatments when mutations arise: the drug that no longer functions can be replaced, and FSC.II can immediately recommend a new combination.

“Drug combinations are conventionally designed using dose escalation,” said Dean Ho, a co-corresponding author of the study and the co-director of the Jane and Jerry Weintraub Center for Reconstructive Biotechnology at the School of Dentistry. “Until now, there hasn’t been a systematic way to even know where the optimal drug combination could be found, and the possible drug-dose combinations are nearly infinite. FSC.II circumvents all of these issues and identifies the best treatment strategy.”

The researchers demonstrated that combinations identified by FSC.II could treat multiple lines of breast cancer that had varying levels of drug resistance. They evaluated the commonly used cancer drugs doxorubicin, mitoxantrone, bleomycin and paclitaxel, all of which can be rendered ineffective when cancer cells eject them before they have had a chance to function.

The researchers also studied the use of nanodiamonds to make combination treatments even more effective. Nanodiamonds — byproducts of conventional mining and refining operations — have versatile characteristics that allow drugs to be tightly bound to their surface, making it much harder for cancer cells to eliminate them and allowing toxic drugs to be administered over a longer period of time.

The use of nanodiamonds to treat cancer was pioneered by Dean Ho, a professor of bioengineering and member of the UCLA Jonsson Comprehensive Cancer Center and the California NanoSystems Institute.

“This study has the capacity to turn drug development, nano or non-nano, upside-down,” he said. “Even though FSC.II now enables us to rapidly identify optimized drug combinations, it’s not just about the speed of discovering new combinations. It’s the systematic way that we can control and optimize different therapeutic outcomes to design the most effective medicines possible.”

The study found that FSC.II-optimized drug combinations that used nanodiamonds were safer and more effective than optimized drug-only combinations. Optimized nanodrug combinations also outperformed randomly designed nanodrug combinations.

“This optimized nanodrug combination approach can be used for virtually every type of disease model and is certainly not limited to cancer,” said Chih-Ming Ho, who also holds UCLA’s Ben Rich Lockheed Martin Advanced Aerospace Tech Endowed Chair. “Additionally, this study shows that we can design optimized combinations for virtually every type of drug and any type of nanotherapy.”

Both Dean Ho and Chih-Ming Ho have collaborated with other researchers and have validated FSC.II’s efficacy in many other types of cancers, infectious diseases and other diseases.

Other co-authors were Hann Wang, Dong-Keun Lee, Kai-Yu Chen and Kangyi Zhang, all of UCLA’s department of bioengineering, School of Dentistry, California NanoSystems Institute and Jonsson Cancer Center; Jing-Yao Chen of UCLA’s department of chemical and biomolecular engineering; and Aleidy Silva of UCLA’s department of mechanical and aerospace engineering.

The work was supported in part by the National Cancer Institute, the National Science Foundation, the V Foundation for Cancer Research, the Wallace H. Coulter Foundation, the Society for Laboratory Automation and Screening, and Beckman Coulter Life Sciences.

In preclinical studies using rodents, they found that stem cells transplanted one week after the completion of a series of chemotherapy sessions restored a range of cognitive functions, as measured one month later using a comprehensive platform of behavioral testing. In contrast, rats not treated with stem cells showed significant learning and memory impairment.

The frequent use of chemotherapy to combat multiple cancers can produce severe cognitive dysfunction, often referred to as “chemobrain,” which can persist and manifest in many ways long after the end of treatments in as many as 75 percent of survivors – a problem of particular concern with pediatric patients.

“Our findings provide the first solid evidence that transplantation of human neural stem cells can be used to reverse chemotherapeutic-induced damage of healthy tissue in the brain,” said Charles Limoli, a UCI professor of radiation oncology.

Study results appear in the Feb. 15 issue of Cancer Research, a journal of the American Association for Cancer Research.

Many chemotherapeutic agents used to treat disparate cancer types trigger inflammation in the hippocampus, a cerebral region responsible for many cognitive abilities, such as learning and memory. This inflammation can destroy neurons and other cell types in the brain.

Additionally, these toxic compounds damage the connective structure of neurons, called dendrites and axons, and alter the integrity of synapses – the vital links that permit neurons to pass electrical and chemical signals throughout the brain. Limoli compares the process to a tree being pruned of its branches and leaves.

Consequently, the affected neurons are less able to transmit important neural messages that underpin learning and memory.

For the UCI study, adult neural stem cells were transplanted into the brains of rats after chemotherapy. They migrated throughout the hippocampus, where they survived and differentiated into multiple neural cell types. Additionally, these cells triggered the secretion of neurotrophic growth factors that helped rebuild wounded neurons.

Importantly, Limoli and his colleagues found that engrafted cells protected the host neurons, thereby preventing the loss or promoting the repair of damaged neurons and their finer structural elements, referred to as dendritic spines.

“This research suggests that stem cell therapies may one day be implemented in the clinic to provide relief to patients suffering from cognitive impairments incurred as a result of their cancer treatments,” Limoli said. “While much work remains, a clinical trial analyzing the safety of such approaches may be possible within a few years.”

The designation means that UC Davis has complied with stringent quality and safety requirements for its computed tomography (CT) scanning practices, and it confirms that UC Davis meets the required radiation-dose standards.

The designation follows a decision by the federal Centers for Medicare and Medicaid Services to recommend CT screening for individuals deemed at high risk for developing lung cancer. Those include men and women who have smoked more than a pack a day for 30 years or two packs a day for 15 years. The screening is limited to individuals over age 55 and up to 77 or 80 depending on the individual’s insurance.

Since Jan. 1, as set forth in the Affordable Care Act, private insurers must cover the screening for people who meet the criteria. The health care reform law stipulates that insurers must provide services recommended by the U.S. Preventive Services Task Force, an independent panel that analyzes data and makes recommendations about health screening.

The task force in December 2013 recommended low-dose CT screening for eligible individuals based on results of the groundbreaking National Lung Screening Trial, which determined that low-dose CT screening reduced the risk of dying from lung cancer in heavy smokers by 20 percent compared to screening with chest X-rays. Data from the trial were published in the New England Journal of Medicine in 2011.

Lung cancer is the third most common cancer and the leading cause of cancer death in the United States. Smoking is the leading cause of lung cancer; about 85 percent of all U.S. lung cancer cases are smoking related. Lung cancer is most commonly diagnosed in people 55 and older.

The American College of Radiology represents more than 37,000 diagnostic radiologists, radiation oncologists, interventional radiologists, nuclear medicine physicians and medical physicists. The organization works to improve, promote and protect the practice of radiology to ensure the quality and safety of patient care.

The UC Davis lung cancer screening program uses a multidisciplinary team of radiologists, thoracic surgeons, pulmonologists, pathologists, medical oncologists and radiation oncologists to develop a patient-centered plan for leading-edge lung cancer care. Individuals interested in lung cancer screening should discuss the pros and cons of the test with their primary care physician, who will, after a shared decision to participate has been reached, refer them to the UC Davis Department of Radiology.

Referrals can be faxed to (916) 703-2254, and screenings can be scheduled by calling (916) 734-0655.

A protein called YAP, which drives the growth of organs during development and regulates their size in adulthood, plays a key role in the emergence of resistance to targeted cancer therapies, according to a new study led by UC San Francisco researchers.

By precisely identifying the mechanism by which elevated levels of YAP promote the survival of cancer cells, the new work points the way to combination therapies that may overcome resistance to individual targeted drugs, the scientists said.

Though cancer drugs aimed at specific genetic mutations have had some success in recent years, most patients who have a good initial response eventually develop resistance to these therapies, most likely because cancer cells engage alternative survival mechanisms that lie outside the biological pathways targeted by the drugs.

Though oncologists have the option of switching to a different targeted drug after resistance takes hold, many cancer researchers believe that a better strategy would be to forestall cancer cells’ eventual escape routes by using customized combinations of targeted drugs at the outset of therapy.

“Instead of trying to figure out why patients have developed resistance after it has emerged, we need to decipher what survival tactic tumor cells will be most dependent on when they are challenged with targeted therapy,” said the senior author of the study, Trever Bivona, M.D., Ph.D., UCSF assistant professor of medicine and a member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC). “We want to learn how to wipe out that alternative survival pathway at the beginning of therapy — to pull the rug out from under those cells right away.”

In the new research, published in today’s (Feb. 9) online issue of Nature Genetics, an international team of scientists led by Bivona used a gene-silencing tool called short-hairpin RNAs (shRNAs) to tamp down the activity, one by one, of more than 5,000 proteins in lung cancer cells that carried cancer-causing mutations in a gene called BRAF. By simultaneously treating the cells with the cancer drug vemurafenib (Zelboraf), which specifically targets faulty BRAF proteins, the researchers were able to determine whether the drug was more effective when the action of other particular proteins was blocked.

These experiments quickly and decisively fingered YAP in vemurafenib resistance, as all six YAP-directed shRNAs employed by the scientists significantly enhanced the drug’s effectiveness at killing BRAF-mutant cancer cells. The researchers saw similar results with trametinib (Mekinist), which targets a BRAF-activated protein called MEK. Working with other types of cancer cells carrying BRAF mutations, including cells from human melanoma, colon, and thyroid cancers, the researchers again found that suppressing YAP enhanced the effectiveness of both vemurafenib and trametinib.

The collective lab-dish results held up in experiments with animal models in which cells from melanoma and colon cancer were injected under the skin of mice and formed tumors: vemurafenib and trametinib were far more effective in treating these tumors when YAP had been suppressed.

The researchers then turned to cells carrying mutations in another important cancer-driving gene, called RAS. Cancers with these mutations are particularly problematic, because the RAS protein is widely considered to be “undruggable”— no effective targeted therapies have been developed for tumors expressing mutant RAS. Like BRAF, the RAS protein also activates MEK, but MEK-targeted therapies have not been particularly effective in patients with RAS-mutant tumors.

After YAP suppression, however, the MEK inhibitor trametinib was highly effective when tested in RAS-mutant lung cancer, melanoma, and pancreatic cancer cells, and also against RAS-mutant lung tumors implanted in animals.

To ensure that these findings were clinically relevant, the authors examined human tumor samples and found that YAP was highly expressed in BRAF- and RAS-mutant lung cancer and melanoma before patients had received any treatment. Moreover, patients whose tumors had higher YAP levels were more likely to have had an incomplete response when treated with a BRAF and/or MEK inhibitor. Finally, YAP levels rose in tumors when patients developed resistance to those therapies.

The researchers found that YAP exerts its effects across a wide variety of cancer types via a single mechanism involving a protein called BCL-xL, which sends out signals that prevent cells from self-destructing. High YAP levels in cancer cells keep BCL-xL activated, overwhelming the ability of targeted drugs to successfully kill off the cells.

Therefore, when vemurafenib or trametinib treatment was combined with inhibitors of BCL-xL, the drugs were much more effective than when either was given alone, indicating that a combined therapy targeting both the MEK and YAP pathways may be effective in overcoming resistance to targeted therapies for many BRAF- and RAS-mutant tumors.

Bivona emphasized that YAP’s role in organ development was first discovered in the fruit fly Drosophila, and he sees the research as a testament to the importance of basic biological research to improving human health. “YAP was the No. 1 hit in our screening process, but it wasn’t much of a leap to think it might be promoting resistance to targeted therapy, because it had been shown to promote organ growth and cell proliferation in other organisms and systems,” he said. “So this work stood on the shoulders of very good, purely basic science.”

Because BCL-xL has widespread roles in the body, however, BCL-xL inhibitors may prove too toxic to be practical, Bivona said, adding that he and colleagues are exploring partnerships with pharmaceutical companies to develop compounds that target YAP directly.

“This is the first paper to establish that YAP is a bona fide mechanism of resistance to RAF and MEK inhibition,” Bivona said, “and it’s exciting to contemplate and plan what we may be able to do with this knowledge to help cancer patients by improving their precision treatment.”

Other UCSF faculty members taking part in the work include Eric A. Collisson, M.D., assistant professor of medicine and HDFCCC member; Martin McMahon, Ph.D., the Efim Guzik Distinguished Professor in Cancer Biology at HDFCCC; and Alain Algazi, M.D., clinical instructor in the Department of Medicine and HDFCCC member. They were joined by scientists from the Catalan Institute of Oncology, Barcelona, Spain; the Hospital Universitario de la Princesa, Madrid, Spain; the Center for Predictive Molecular Medicine, Chieti, Italy; the Memorial Sloan Kettering Cancer Center; the New York University Cancer Institute; the Vall dHebron Institute of Oncology, Barcelona, Spain; Massachusetts General Hospital; and MD Anderson Cancer Center.

The work was supported by funds from an NIH Director’s New Innovator Award to Trever Bivona, the Howard Hughes Medical Institute, the Doris Duke Charitable Foundation, the American Lung Association, the National Lung Cancer Partnership, the Sidney Kimmel Foundation for Cancer Research, and the Searle Scholars Program.

“Smoking of parents is by itself a risk factor for diabetes, independent of obesity or birth weight.”

Credit: iStock

By Michele La Merrill and Kat Kerlin, UC Davis

Children exposed to tobacco smoke from their parents while in the womb are predisposed to developing diabetes as adults, according to a study from the University of California, Davis, and the Berkeley nonprofit Public Health Institute.

In the study, published today (Feb. 9) in the Journal of Developmental Origins of Health and Disease, women whose mothers smoked while pregnant were two to three times as likely to be diabetic as adults. Dads who smoked while their daughter was in utero also contributed to an increased diabetes risk for their child, but more research is needed to establish the extent of that risk.

“Our findings are consistent with the idea that gestational environmental chemical exposures can contribute to the development of health and disease,” said lead author Michele La Merrill, an assistant professor of environmental toxicology at UC Davis.

The study analyzed data from 1,800 daughters of women who had participated in the Child Health and Development Studies, an ongoing project of the Public Health Institute. The CHDS recruited women who sought obstetric care through Kaiser Permanente Foundation Health Plan in the San Francisco Bay Area between 1959 and 1967. The data was originally collected by PHI to study early risk of breast cancer, which is why sons were not considered in this current study.

In previous studies, fetal exposure to cigarette smoke has also been linked to higher rates of obesity and low birth weight. This study found that birth weight did not affect whether the daughters of smoking parents developed diabetes.

“We found that smoking of parents is by itself a risk factor for diabetes, independent of obesity or birth weight,” said La Merrill. “If a parent smokes, you’re not protected from diabetes just because you’re lean.”

The study was supported through funding from the National Institute of Environmental Health Sciences, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the California Breast Cancer Research Program Special Research Initiative.